1. Field of the Invention
Embodiments of the invention generally pertain to the field of microfluidics, more particularly to laminated polymeric microfluidic structures and to methods for laminating polymeric microfluidic structures and, most particularly to latent solvent-based microfluidic apparatus, methods and applications.
2. Description of Related Art
The technology of manipulating minute volumes of biological and chemical fluids is widely referred to as microfluidics. The realized and potential applications of microfluidics include disease diagnosis, life science research, biological and/or chemical sensor development, and others appreciated by those skilled in the art.
A microfluidic structure including a substrate having one or more microfluidic channels or pathways and a cover plate (of a similar or different thickness as the substrate or thin film) or a second or more substrates, films, membranes, etc., some of which may contain fluid pathways, reservoirs, etc. that may or may not be interconnected, may commonly be referred to as a microfluidic chip. Highly integrated microfluidic chips are sometimes called ‘labs on a chip’. Inorganic microfluidic chips having substrates made of glass, quartz or silicon have advantageous organic solvent compatibilities, high thermal and dimensional stability and excellent feature accuracy. These chips are typically fabricated using well-established microfabrication technologies developed for the semiconductor industry. However, the material and production costs of the inorganic chips may become prohibitively high especially when the fluidic pathway(s) requires significant area or the chip has to be disposable. In addition, many established biological assays were developed compatible with the surface properties of polymeric substrates. The research effort required to redevelop these assays on inorganic surfaces would require significant time and resource investments.
As an alternative to inorganic microfluidic structures such as those referred to immediately above, microfluidic structures or devices can also be made from elastomeric materials (e.g., PDMS, silicone rubber (RTV))). Examples of such devices are disclosed, e.g., in Mathies et al., U.S. Pat. No. 7,445,926; K. Hosokawa, R. Maeda, A pneumatically-actuated three-way microvalve fabricated with polydimethylsiloxane using the membrane transfer technique, J. Micromech. Microeng. 10 (2000) 414-420. Elastomeric microfluidic structures have advantageous low material costs and the potential for mass production. However, the fabrication of elastomeric/polymeric microfluidic chips presents a variety of challenges. For example, microfluidic chips may contain sealed microstructures. They can be formed by enclosing a substrate having a pre-fabricated fluid pathway or other microfeatures with a thin cover plate, or with one or more additional substrates to form a three-dimensional fluid network. The pathways or other microstructures have typical dimensions in the range of micrometers to millimeters. This multilayer microfluidic structure is integrated, or may be joined together by various conventional techniques. These techniques include thermal, ultrasonic and ‘strong’-solvent bonding well known in the art. As used herein and understood in the art, the effective use of a ‘strong-solvent’ bonding agent does not depend on thermal activation conditions or other environmental factors; rather, strong-solvents, per se, chemically melt the polymeric surface that they contact allowing two surfaces to be permanently attached together. Unfortunately, these techniques can significantly alter the mated surfaces and detrimentally distort or completely block the microfluidic pathways. This can be due, for example, to the low dimensional rigidity of polymeric materials exposed to strong-solvent bonding conditions.
The use of adhesives for lamination may circumvent some of these potential difficulties by avoiding the use of excessive thermal energy or a ‘strong’ organic solvent. However, the introduction of an adhesive layer to a wall surface of an enclosed fluid pathway can cause other fabrication and/or application problems. Commercially available adhesives tend to be conforming materials with typical applied thicknesses of 12-100 micrometers. The compressive force required to produce a uniform seal between component layers will often extrude the adhesive into the fluid pathways resulting in microchannel dimensional alteration or obstruction. An additional potential problem with using adhesives is the formation of an adhesive wall within the enclosed microstructure. The presence of this dissimilar material makes uniform surface modification of the microstructure difficult. Furthermore, the manipulation or patterning of an adhesive layer is difficult, limiting the use of the adhesives to uniform continuous sheets or layers between two opposing planar surfaces. This restricts fluidic communication through a network to one planar surface, as the fluid cannot flow through the adhesive layer, preventing the use of a more versatile three-dimensional space.
The use of a strong organic solvent to join two or more discrete, non-elastomeric (or ‘rigid’ as opposed to ‘rubbery’ elastomeric characteristics) plastic parts is a well known practice in the art. In solvent welding, as this process is referred to, lamination solvents work by aggressively penetrating the macromolecular matrix of the polymeric component. This loosens the macromolecule-to-macromolecule bonds, uncoiling or releasing them from their polymer network to generate a softened surface. When two opposing softened surfaces are brought into close proximity, new macromolecular interactions are established. After the solvent evaporates there is a newly formed macromolecular network at the bonded interface with mechanical strength defined by the force of the macromolecular interaction. Exemplary strong organic solvents used for plastic component lamination include ketones (acetone, methylethyl ketone or MEK), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane), ether (tetrahydrofurane or THF) or aromatic molecules (xylene, toluene) and others known by those skilled in the art. It is also known, however, that solvents are not universally solvent. Solvent ability depends upon the particular material to which it is applied as well as to the environmental conditions present during the application such as temperature, humidity, processing conditions, surface conditions (roughness, chemical modification, treatment or functionalization) etc.; thus water, the ‘universal solvent,’ will never be capable of gluing two plates of glass together in the context of ‘solvent welding’.
The use of the aforementioned ‘strong’ solvents for bonding microfluidic chips with layers composed of polystyrene, polycarbonate or acrylic is problematic. All of the solvents known to be used in the field of solvent bonding are “strong” (as defined by their ability to dissolve the polymeric substrate) organic solvents. That is, these solvents tend to over-soften or dissolve the surface of the substrates during the bonding process even under ‘normal,’ i.e., ambient) conditions. The use of these strong solvents may damage the microfluidic structure by completely erasing, blocking or destroying the tiny fluid pathways when the layers are contacted. Acetone, dichloromethane or xylene, for example, begin to dissolve a polystyrene sheet within seconds of application at room temperature. Although it is possible to weaken the solvent strength by mixing the solvent with “inert” solvents such as methanol or ethanol, the resulting bond often does not provide a satisfactory result.
The contemporary patent literature discloses using thermal bonding, thermal-melting adhesive, liquid curable adhesive, and elastomeric adhesive approaches to enclose two opposing microfluidic structure surfaces of the same or different materials. It is suggested that these methods are applicable to the fabrication of microchannels of various shapes and dimensions. It is apparent, however, that these approaches rely on stringent control of the fabrication and process conditions, which may result in unacceptable fabrication throughput and production yield.
Another reported technique suggests that the quality of a thermally laminated polymeric microchannel can be drastically improved if the opposing substrates have different glass transition temperatures. While this approach may provide a way to retain microstructural integrity during thermal bonding, the success rate will rely on precise process control. Consequently, its application to microfluidic chip manufacturing is restricted.
A recent publication describes a method of creating a plurality of relief structures along the length of a microfluidic channel wall, projecting from the opposing surface in the non-functional area of the substrate. Subsequent deposition of a bonding material fills this relief structure, completing the bond. This method allegedly can increase the manufacturing yield of adhesive bonded microfluidic devices. The significant challenge of dispensing the correct volume of bonding material into the relief structures is not addressed. The necessary control of the small volume of bonding material does not lend itself to high production yields.
As disclosed herein and embodied in the claimed inventions of the priority documents referenced above, a ‘weak’ solvent such as but not limited to acetonitrile was utilized to irreversibly bond a thin (e.g., 25 μm) non-elastomeric membrane to a thicker (e.g., 100 μm) non-elastomeric substrate having microchannels in a surface thereof generally via introduction of the weak solvent onto or between the surfaces to be bonded and then thermally activating the system to form the bond. As mentioned, this proved to be effective, e.g., when acetonitrile was used to bond a thin polystyrene membrane to a thicker polystyrene, channeled substrate.
Two important considerations in the commercial success of microfluidics are cost-effective disposability and material compatibility of the chip with the fluid(s) running through it and the analyses being performed. Effects such as, but not limited to, clouding or the reduction of optical transparency may be highly deleterious. For example, polystyrene may not be the chip/system material of choice for all applications. Furthermore, when two polymeric microfluidic layers are solvent bonded where one layer must remain unbonded over a region of the other layer (e.g., a membrane over a valve seat in a substrate), residual solvent can collect around the perimeter of the unbonded region causing a deterioration of the material in the perimeter region that results in a bad seal and subsequent leakage conditions and failure of the microfluidic chip.
In view of the foregoing, the inventors have recognized the benefits and advantages of the ability to select and use the most efficacious microfluidic chip materials in a particular application that still meet the practical requirements of disposability, ease of manufacture, structural integrity, and other considerations known in the art. Accordingly, embodiments of the invention are directed to microfluidic structures and fabrication methods that address the recognized shortcomings of the current state of technology, and which provide further benefits and advantages as those persons skilled in the art will appreciate.